This invention relates to new benzene-sulphonamide derivatives and to their non-toxic salts as well as to their therapeutic uses.
The new benzene-sulphonamide derivatives, according to the invention, are represented by the general formula (I): 
in which:
X represents a nitro, cyano, halogen group, eventually radioactive.
Y1 represents a secondary or tertiary amino group, a sulphur or an oxygen;
Y2 represents a nitrogen, an oxygen or a xe2x80x94NH group;
Z represents oxygen, sulphur, xe2x80x94Nxe2x80x94CN or xe2x80x94CHxe2x80x94NO2; and
R1 and R2, which can be identical or different, represent each independently a linear or ramified alkyl group, saturated or unsaturated wit 2 to 12 carbon atoms, an alicyclic group, saturated or unsaturated with 3 to 12 carbon atoms, eventually radioactive, an aryl group, substituted or not by one or several alkyl groups in C1-C4, nitro, cyano, trifluoromethyl, carboxy and halogen, or an arylalkyl group,
or R1 and/or R2 form with Y1 and/or Y2 a 5 to 7 membered heterocyclic group, saturated or unsaturated chains. with the exception of derivatives for which X is a nitro group,. Y1 represents a secondary amine group (xe2x80x94NHxe2x80x94), Y2 represents a xe2x80x94NH group, Z an oxygen, R2 an isopropyl and R1 an element selected in the group comprising (m-toluyl, phenyl and cyclooctyl) and with the exception of N-[(2-cyclooctylamino-5-cyanobenzene)sulfonyl]Nxe2x80x2-isopropyl urea.
This invention refers also to optical isomers of benzene-sulphonamide derivatives covered by the formula (I) or to salts pharmacologically acceptable of these derivatives
This invention refers also to salts of these derivatives, covered by the formula (I), by addition of non-toxic basis, for example to sodium and potassic salts, to salts with an organic acid, as an amino acid such as the lysine, the arginine, for example.
When, in the general formula (I), one has an asymmetrical carbon atom (as for example when R1 and/or R2 represent an arylalkyl group), the invention refers as well as to pure optical isomers than to the racemic mixture.
Preferred classes of compounds according to the formula (I) are, especially, those in which the X represents a nitro, cyano, bromo or iodo group, Y1 represents a xe2x80x94NH group, Y2 represents a xe2x80x94NH group or an oxygen atom and R1 and R2 represent each independently an ethyl, butyl, tert-butyl propyl, isopropyl, pentyl, hexyl, heptyl, octyl, decyl, amyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl, 2-cyclohexenyl, m-toluyl, o-toluyl, p-toluyl, phenyl, allyl, adamantyl, norbornyl, caproyl, 3-carboxyphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, furfuryl, benzyl or 1-phenylethyl group.
Another preferred class of these compounds is that in which R2 and Y2 form a homopiperidin group and that in which R1 and Y1 form a morpholin or homopiperidin group.
Still another particularly interesting class is that made by radioactive derivatives of the invention, and especially the derivatives in which X represents radioactive iodine, such that the 126I and its radioactive isotopes 125I and 131I, and those in which R1 represents a saturated alicyclic group or unsaturated group with a tritium hydrogen in positions 2 and/or 3 of the cycle.
As one will see hereinafter in a more detailed way, the derivatives complying with the formula (I) are very useful in the prevention and/or treatment of illnesses involving the thromboxan A2 at different levels, and especially in the cardiovascular and blood domains, pulmonary domain, reproduction domain and renal domain. They constitute also an excellent radiolabelled pharmacological tool of the thromboxan A2 receptors.
The present invention concerns, therefore, also the use of these benzene-sulphonamide derivatives and their salts for drug manufacture for the treatment and/or the prevention of the illnesses involving the thromboxan A2 as well as as radiolabelled pharmacological tools of the thromboxan A2 receptors and of the pharmaceutical compositions containing these derivatives, these latter or their salts being used alone or in combination with excipients and/or other therapeutic agents having a similar or different activity.
The active compounds of the invention can be administered, according to the invention, under the form of a pharmaceutical composition, in association with different pharmaceutical excipients and this by oral, parenteral, rectal and topical way.
For the oral administration, one will use pills, granules, tablets, capsules, solutions, syrups, emulsions and suspensions containing classic excipients or additives in clinical pharmacy.
By parenteral way, the salts of active products could be administered in aqueous solution for example.
For the rectal administration, one will use suppositories and, by topical way, lotions, unguents, pomades, aerosols or nebulizers.
The active products can be used alone or in combination with other active products having a similar or different activity.
Among the compounds which give, in pharmaceutical use, very interesting results, we have to consider those in the formula (I), in which X represents a NO2 or iodine group,
Y1 represents a secondary amino group,
Y2 represents a xe2x80x94NH group,
Z represents an oxygen group, sulphur group or xe2x80x94Nxe2x80x94CN group, and R1 represents a cyclohexyl group, cycloheptyl group or cychlohexen-2-yl group, and
R2 an isopropyl group, tert-butyl group, pentyl group or homopiperidin group,
and particularly considering the following compounds:
N-[(2-cyclohexylamin-5-nitrobenzene)sulfonyl]Nxe2x80x2-tert-butyl urea,
N-cyano-Nxe2x80x2-[(2-metatoluylamin-5-nitrobenzene)sulfonyl]homopiperidinoamidine,
N-[(2-cycloheptylamin-5-nitrobenzene)sulfonyl]Nxe2x80x2-cyclohexyl thiourea, and
N-[(cyclohexen-2-yl)-5-iodobenzene)sulfonyl]Nxe2x80x2-pentyl urea.